This U01 grant application in response to RFA - AA-12-007 for Translational Research in Alcoholic Hepatitis is to test novel therapeutic approaches and reveal new biomarkers in alcoholic hepatitis. Alcoholic hepatitis carries high mortality and the current standard therapy with steroids is suboptimal. Because the pathogenesis of alcoholic hepatitis involves complex interactions between innate immune activation, impaired intestinal permeability and activation of cellular death pathways, we hypothesize that clinically effective new therapy should include combined therapeutic approaches that target all critical components of disease pathology. Based on preclinical data in mice and human safety, we propose to compare standard of care with steroids with a combination of pentoxiphylline plus IL-1 receptor antagonist (anakinra) plus zinc treatment in patients with acute severe alcoholic hepatitis. In patients with moderate alcoholic hepatitis the efficacy of probiotic therapy will be tested against placebo. This U01 application build on the collaboration of leading scientists in alcoholic liver disease with clinical, translational and basic research expertize from the University of Massachusetts, Cleveland Clinic, University of Louisville and UT Southwestern Medical Schools with the goal to test novel therapies, discover unique disease stage- and therapeutic response-specific biomarkers using dynamic bench-to-bedside and bedside-to-bench approaches. Biomarker analyses will include serum microRNAs, unique breath and urine markers to establish new predictors of disease outcome and treatment strategies. Preclinical studies in a mouse model will test candidate compounds to inhibit complement activation and strategies through FXR activation that may prove to be clinical candidates in the latter half of the project i the clinical trial component. To enhance the scientific potential and translational impact of this consortium, the lead PIs recruited participation of leading experts for the translational projects including Victor Ambros, the discoverer of microRNAs and Charis Eng, an internationally recognized expert in integrative genomic analysis for diseases. The Advisory Board will bring together Bruce Beutler, 2011 Nobel Laureate for discoveries in innate immunity, Willis Maddrey, the lead clinical expert in alcoholic hepatitis in the USA, Anna Mae Diehl, a highly distinguished leader in the field of steatohepatitis, and Christopher Day from the UK who is a physician scientist in the UK-European steatohepatitis translational research field. Participating investigators and institutions are as follows: Dr. Arthur McCullough Cleveland Clinic Dr. Laura Nagy Cleveland Clinic Dr. Craig McClain University of Louisville Dr. Mack C. Mitchell, Jr., M.D. U. T. Southwestern Medical School Dr. Gyongyi Szabo University of Massachusetts Medical School PUBLIC HEALTH RELEVANCE: It is estimated that there are 17.6 million alcoholic individuals in the US and 140 million worldwide; while not all alcoholics develop symptomatic liver disease, about 12,109 deaths/year are attributed to alcoholic liver disease in the United States. Alcoholic hepatitis is the most severe form of ALD and has high morbidity and limited treatment options. This application is for leading experts in the field of alcoholic liver research to test novel therapies in clinical trials and to discover and validate clinically relevant biomarkers using innovative translational research tools.